The NF1 tumor suppressor regulates PD-L1 and immune evasion in melanoma
Hotspot BRAF, hotspot NRAS, and NF1 loss-of-function mutations are found in approximately 50%, 25%, and 15% of cutaneous melanomas, respectively. Compared to mutant BRAF and NRAS, the role of NF1 loss in melanoma remains understudied. NF1 has a RAS GTPase-activating protein (GAP) function; however, studies also support NF1 RAS-independent tumor-suppressor functions. Recent reports indicate that patients with NF1 mutant melanoma have high response rates to anti-PD-1 immune checkpoint inhibitors (ICIs) for reasons that are not entirely clear. Here, we present data demonstrating that NF1 interacts with PD-L1. Furthermore, NF1 loss in melanoma lines increases PD-L1 cell surface expression through a RAS-GAP-independent mechanism. Co-culture experiments demonstrate that NF1 depletion in melanoma increases resistance to T cell killing, which can be abrogated with anti-PD-1/PD-L1 ICIs. These results support a model whereby NF1 loss leads to immune evasion through the PD-L1/PD-1 axis, providing support for the examination of anti-PD-1 therapies in other NF1 mutant cancers.
Authors
- Alan Spatz (ORCID: https://orcid.org/0000-0003-3020-1420)
- Ari N. Meguerditchian (ORCID: https://orcid.org/0000-0003-4798-8135)
- Béatrice Wang
- Simon Turcotte (ORCID: https://orcid.org/0000-0002-0978-736X)
- Dan Moldoveanu (ORCID: https://orcid.org/0000-0002-1191-9798)
- Tiffany Lin
- Réjean Lapointe (ORCID: https://orcid.org/0000-0002-1871-5878)
- Kevin Petrecca (ORCID: https://orcid.org/0000-0002-8140-6402)
- Sarkis Meterissian (ORCID: https://orcid.org/0000-0002-9586-3583)
- T. Martin Schmeing
- Mathieu Lajoie (ORCID: https://orcid.org/0000-0001-9162-086X)
- Diana Berry (ORCID: https://orcid.org/0000-0003-4954-4140)
- Itai Sharon (ORCID: https://orcid.org/0000-0002-5844-3133)
- Anne‐Marie Mes‐Masson (ORCID: https://orcid.org/0000-0002-6498-266X)
- Shivshankari Rajkumar (ORCID: https://orcid.org/0000-0002-7620-2464)
- Françis Rodier (ORCID: https://orcid.org/0000-0003-2523-309X)
- Daméhan Tchelougou (ORCID: https://orcid.org/0000-0002-2123-6632)
- John Stagg (ORCID: https://orcid.org/0000-0001-7833-4228)
- Wilson H. Miller (ORCID: https://orcid.org/0000-0002-7408-1574)
- Kevin Watters
- Senthil Kumar K. Sakthivel
- Catalin Mihalcioiu (ORCID: https://orcid.org/0000-0003-4010-2012)
- Antoine Bernard (ORCID: https://orcid.org/0000-0002-6932-5685)
- Keith Richardson (ORCID: https://orcid.org/0000-0001-5224-0688)
- Sandy Pelletier (ORCID: https://orcid.org/0000-0002-5869-424X)
- May Chergui
- Rahima Jamal
- Marie‐Christine Guiot
- Ian R. Watson
- Yael Ripstein
Institutions
- Montreal Neurological Institute and Hospital (CA)
- McGill University Health Centre (CA)
- Centre Hospitalier de l’Université de Montréal (CA)
- University of Manitoba (CA)
- McGill University (CA)
- Université de Montréal (CA)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-03-01
- DOI
- https://doi.org/10.1016/j.celrep.2025.115365
- Citations
- 5
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 5.23
Funders
- Melanoma Research Alliance
- Canada Research Chairs
- Canadian Institutes of Health Research